2Topics Definitions of failure and classification Aetiology- Acute versus acute on chronicBasic diagnostic workupLiver biopsy in the contextACLF-Ethical dilemma- HDU admissionTreatment of complicationHepatic encephalopathyRenal failureGI bleedInfectionCoagulopathyAetiology specific treatmentOrgan supportLiaison with Transplant centre
3The mortality rate for acute liver failure ranges between 56% and 80%
4Abnormal LFT is NOT ALF Dear Doctor Patient’s bilirubin is 600 and has liver failure- kindly urgently seeFamily was told transplant may be necessary
5Formal diagnosis of acute liver failure An increase in PT by 4-6 seconds (INR>1.5)And the development of hepatic encephalopathy (HE).In a patient without pre-existing cirrhosis and with an illness of less than six months duration.
6UK incidence of cirrhosis 17 per 100,000 Prevalence of cirrhosis is 76 per 100,000ALF incidence is 1-6 per million per year
7aCLFThis entity is quite common- background of cirrhosis. Innocent precipitating event culminates in MOFEventsToxins (alcohol!)Vascular (hypotension- GI bleed, dehydration, Portal vein thrombosis)Infection (SBP)HCC
21Paracetamol Overdose Phase I – 0-24h Anorexia, nausea and vomiting, malaiseLFT derrangement at 12hPhase II – 18-72hRUQ painLFT derrangmentPhase III – 72-96hCentrilobar necrosisLiver failurePhase IV – 4d-3wkRecovery, transplant or deathNo chronic state21
22When to pick up the phone D2-pH <7.3INR>3Cr >200HypoglycaemiaD3-HECr>200INR >4.5D4-Any rise in INRCr >250
23Definition: HRS ARF in a patient CLD, severe alcoholic hepatitis or ALF from any causeEnd-stage of reduction in renal perfusion induced by increasingly severe hepatic injury.
24Sinusoidal portal hypertension, in the presence of severe hepatic decompensation Leads to splanchnic and systemic vasodilatation-role of NODecreased effective arterial blood volumeActivation of RAS, and vasopressin aimed at restoring arterial filling pressure.Renal vasoconstriction increases counterbalanced by the intrarenal prostaglandins.When this balance is lost renal hemodynamics worsens, and hepatorenal syndrome develops
26HRS Major criteria Minor criteria Chronic or acute hepatic disease and liver failure with portal hypertensionSerum creatinine level >133 micromoles/LAbsence of shock, ongoing bacterial infection, recent use of nephrotoxic drugs, excessive fluid or blood lossNo sustained improvement in renal function after volume expansion with 1.5 L isotonic saline solutionNo Proteinuria (Protein<500 mg/day) and no ultrasonographic evidence of renal tract or parenchymal diseaseMinor criteriaUrine volume <500 mL/dayUrine sodium <10 mEq/LUrine osmolality greater than plasma osmolalityUrine red blood cell count <50 per high-power fieldSerum sodium <130 mEq/L
27Classification of HRSType I is defined by a rise in creatinine level to over 221 micromoles/L in less than 2 weeksMedian survival of 2 weeksType II is defined as less severe renal insufficiency; it is principally characterized by ascites that is resistant to diuretics.Median survival of 3-6 months.
28Vasoactive Medical treatment Terlipressin bolus(0.5mg/4h)-increase every 3 days if no response to 1-2mg/4hGiven until creatinine normalizes or for 15 daysAlbumin 1g/kg on day1( one bag of HAS contains 20grams)20-60g/d thereafter
29Step by step guide : Normal renal us Normal urine dipsix – no RBC cast No nephrotoxic drugsFluid challengeSpot Na and serum NaSerum and urine osmolalityUrine outputPRERENALHRSATNSpot Na<10>30Urine sedimentNilPositiveFluid challengeResponds
30The stages of HE- West Haven criteria: Stage 0. Lack of detectable changes in personality or behaviour. Asterixis absent.Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria or depression. Asterixis can be detected.Stage 2. Lethargy or apathy. Disorientation. Inappropriate behaviour. Slurred speech. Obvious asterixis.Stage 3. Gross disorientation. Bizarre behaviour. Semistupor to stupor. Asterixis generally absent.Stage 4. Coma.
31HE- Four compatible theories Cerebral vasomotor dysfunctionOedema secondary to ammonia toxicityInflammation due to SIRSputative benzodiazepine-like molecules
32The pathophysiology of HE A large body of work points at ammonia as a key factor in the pathogenesis of HE.Portal ammonia is derived from both the urease activity of colonic bacteria and the deamidation of glutamine in the small bowel.The intact liver clears almost all of the portal vein ammonia, converting it into glutamine and preventing entry into the systemic circulation.Ammonia- astrocyte swelling in brain
33Patients with grade II HE should be managed in a HDU environment. Grades III and IV HE requires definitive airway protection and appropriate monitoring.Grade IV HE is strongly associated with elevated levels of serum ammonia, a high incidence of raised intracranial pressure and the development of uncal herniation.
35In acute and chronic liver disease, increased arterial levels of ammonia are commonly seen. However, correlation of blood levels with mental state in cirrhosis is inaccurate.
36Lactulose is a first-line pharmacological treatment of HE. Lactulose – reaches colon, where bacteria will metabolize the lactulose to acetic acid and lactic acid.This lowers the colonic pHformation of the non-absorbable NH4+ from NH3,Other effects like catharsis also contribute to the clinical effectiveness of lactulose.
37LactuloseFor acute encephalopathy, lactulose (ingested or via nasogastric tube), 45 ml p.o.,Is followed by dosing every hour until evacuation occurs.Target -three soft bowel movements per dayIf response to disachharide is poor- add antibiotic (metronidazole or rifaximine after 48Hrs) to reduce enteric bacterial mass.
38If patient is refusing oral lactulose prescribe phosphate enemas TDS! An excessively sweet taste, flatulence, and abdominal cramping are the most frequent subjective complaints with this drug.
39The coagulopathy of liver disease Failure to produce clotting factors II, V, VII and IXFailure of the diseased liver to clear activated clotting factors.Degree of hypersplenism and thrombocytopaenia often adds to the coagulopathy, especially if disseminated intravascular coagulation (dic) also co-exists.The degree of coagulopathy is a measure of severity of liver disease and of patient prognosis.Routine correction of coaguloapthy is therefore NOT indicated unless active bleeding or planned interventions require it
40Sepsis Infection may be the initiating event of liver failure, Intercurrent sepsis is also a common problem .Impaired immune function, in part secondary to reduced complement factor production andImpaired neutrophil, leukocyte and monocyte function, can result in delayed presentation of clinical signs of infection.The interventions required for diagnosis and management of liver disease also increase patient vulnerability to invasive infection.
41Role of prophylactic antibiotic Only patients who have an episode of gastrointestinal bleedingor an episode of spontaneous bacterial peritonitis (SBP) have been shown to have a significant outcome benefit from prophylactic antibiotics.
42In presence of sepsisChoice of antibiotic should be guided by local microbiological surveillance.The high incidence of mycoses - low threshold for antifungal.Regular microbiological surveillance
43Role of NAC Efficacy of NAC is well established in PCM induced ALF Non PCM ALF – role of NAC is controversial175 patients of non PCM ALF received NACTransplant free survival at 3 weeks was 52% in NAC group compared to 30% in placebo arm ( only with coma grade of 1-2)United States ALF study group- overall was 70% vs 66%
45Extracorporeal Liver Assist Device (ELAD) Hepatocyte bioreactor- hepatoma cells cultivated on the exterior surface of semipermeable hollow fibresMARS (molecular adsorbent recirculating system)
46ELAD Both reduce the level of bilirubin, bile salt ammonia etc However no of patients dying or requiring liver transplant did not improveDevices remain experimental and large-scale phase two and three trials are awaited
47Summary• The mortality rate for acute liver failure ranges between 56% and 80%• The main role of intensive care therapy is multi-organ support• The commonest cause of acute liver failure in the western world is paracetamol toxicity• Hepatic encephalopathy is no longer the main cause of death but it’s detection and management requires sophisticated cardiovascular and cerebral monitoring• Hepatorenal failure is due to the complex interplay between splanchnic, renal and systemic circulatory responses to liver failure. Terlipressin has been shown to be of use in its treatment• Novel hepatic replacement therapies are under development but definitive studies as to their efficacy are, as yet, unpublished.